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2024 AACR重磅摘要|海创药业6项全球首创肿瘤药物研究成果亮相发布!

发表时间:2024-04-11 来源:海创药业 阅读:2320

海创药业(688302.SH)6项研究成果在2024年美国癌症研究协会(AACR)年会Late-Breaking Research(重磅摘要)环节上发布。转化医学部与生物部负责人李景博士和商务部负责人Agustin de la Calle博士出席了本届AACR年会并作项目成果介绍。


*李景博士与Agustin de la Calle博士现场照片*


2024年度美国癌症研究协会(American Association for Cancer Research, AACR)年会作为癌症研究界的焦点,邀请了来自世界各地的癌症科学家,共同分享和讨论肿瘤领域的最新科学和医学研究成果。AACR年会于当地时间2024年4月5日至10日在美国加利福尼亚州圣地亚哥举行。Late-Breaking Research是AACR年会中备受瞩目的会议环节,该环节主要展示在肿瘤治疗领域中最具有创新价值和临床潜力的研究。海创药业本次6项研究成果在Late-Breaking Research环节发布,标志着公司产品管线的创新力及临床潜力得到国际认可。


*李景博士讲解项目现场照片*



海创药业6项研究涉及乳腺癌、前列腺癌、恶性血液肿瘤、骨髓纤维化等适应症,6项临床前研究摘要成果如下:



01 HP518


摘要标题:

HP518, an oral AR-targeting PROTAC for the treatment of AR positive triple negative breast cancer with a novel mechanism of action


摘要作者:

J. Li, H. Yuan, K. Chen, Y. Huo, G. Liu, W. Du, X. Li;

Hinova Pharmaceuticals, Chengdu, China


摘要全文:

Triple negative breast cancer (TNBC) accounts for 15-20% of all breast carcinomas and has poor prognosis. Chemotherapy is the mainstay treatment for TNBC patients, yet with limited clinical benefit. Androgen receptor (AR) is expressed in approximately 50% of TNBC tumors and thus the anti-androgen therapy could be a promising solution for the treatment of AR TNBC. Nevertheless, AR inhibitors including enzalutamide and bicalutamide or the androgen biosynthesis inhibitor abiraterone have failed to demonstrate satisfying anti-tumor activity in clinical trials. We have discovered HP518, an AR-targeting PROTAC (proteolysis targeting chimera) that induces potent degradation of both the wild-type AR and AR mutants. HP518 is currently under the clinical development for the treatment of mCRPC. Here we report the preclinical data on HP518 for the treatment of AR TNBC. HP518 robustly degrades AR in multiple TNBC cell lines with a half-maximal degradation concentration (DC ) < 1 nM. HP518 strongly inhibits AR TNBC cell growth, whereas the AR inhibitor enzalutamide does not show significant antiproliferative effect on these cells in the presence or absence of androgen. Consistent with the in vitro results, HP518 significantly and dose-dependently inhibits tumor growth in MDA-MB-453 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models. PI3KCA activating mutations are frequently expressed in AR TNBC. HP518 in combination with alpelisib, a PI3Kα inhibitor shows a synergistic anti-tumor activity. Mechanistically, HP518, but not AR inhibitor enzalutamide downregulates the mRNA expression levels of a set of DNA replication-related genes in AR TNBC cells, indicating a novel and ligand-independent role for AR in regulating growth of AR TNBC cells. Therefore, HP518, an AR-targeting PROTAC degrader holds great potential to fulfill the unmet clinical needs for the AR TNBC therapy. Selected pre-clinical data will be presented. HP518 structure will not be disclosed.



02 HP568


摘要标题:

Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer


摘要作者:

W. Du, Z. Tu, D. Qin, H. Li, J. Duan, S. Liu, M. Zhang, Z. Nie, Z. Yuan, J. Li, X. Li;

Hinova Pharmaceuticals, Chengdu, China


摘要全文:

Breast cancer remains an unmet medical need. It has become the most occurring and deadliest cancer for women globally. Estrogen receptor (ER) is expressed in 75% of breast cancers and has the key role in tumorigenesis and progression of ER breast cancers. Endocrine treatments that target ER are the mainstay therapies for the ER breast cancers, yet drug resistance unavoidably develops due to mutations in the ER gene. The ER-targeting proteolysis targeting chimera (PROTAC) degrader is an emerging new modality that interrupts the ER signaling through degradation of ER and offers unprecedented potential for solving the endocrine resistance. We have discovered HP568, an ER-targeting PROTAC that is highly potent against both the wild-type ER and ER mutants. HP568 has a favorable ADME profile that is superior to known competitor ER-targeting PROTAC. In the head-to-head comparison efficacy studies, HP568 has demonstrated the dose-dependent and superior efficacy that is well consistent with the drug exposure profile and PD biomarkers. HP568 also shows a synergetic effect in combination with a CDK4/6 inhibitor. HP568 is clean in the secondary pharmacology profiling, and well tolerated in animal tox studies. HP568 is under the preclinical development and has the potential to be the best-in-class ER-targeting degrader. HP568 structure will not be disclosed.



03 HP537


摘要标题:

Discovery of HP537, a potent and selective p300/CBP inhibitor for the treatment of hematologic malignancies


摘要作者:

J. Li, Z. Tu, J. Peng, L. Fan, H. Yu, F. Wang, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China


摘要全文:

E1A-binding protein P300 (p300) and its paralog CREB binding protein (CBP) are key acetyl transferases (HAT) and transcriptional co-factors. p300/CBP bromodomain (BRD) inhibition reduces acetylation of H3K27 at enhancers, leading to suppression of enhancer-driven gene expression, such as MYC and IRF4 that are critical for the initiation, progression, and chemoresistance of hematological malignancies. Thus, p300/CBP inhibition is a highly potential therapeutic strategy for the treatment of hematological malignancies, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and leukemia. We have discovered HP537 that competitively inhibits an acetylated peptide substrate to bind BRD of p300/CBP with IC50 < 5 nM. HP537 does not inhibit the enzymatic activity of HAT domain of p300/CBP and HAT1, nor has binding affinity for other BRD containing proteins including BRD4 and BRD9. HP537 inhibits proliferation of a wide range of cell lines derived from MM, leukemia and lymphoma with IC50 values ranged from 0.01 μM to 0.4 μM. Protein expression levels of acetylated H3K27, c-Myc and IRF4 are significantly decreased by HP537 in MM, NHL and acute myelogenous leukemia (AML) cell lines in a dose- and time-dependent manner. HP537 robustly and dose-dependently inhibits tumor growth in OPM-2 (MM), MOLM-16 (AML), and KARPAS-422 (NHL) cell line derived tumor xenograft (CDX) mouse models. Down-regulation of c-Myc and IRF4 are also observed in the tumor samples. In conclusion, HP537 is a novel, potent and selective inhibitor of p300/CBP BRD. The pre-clinical data supports the clinical development of HP537 for the treatment of hematological malignancies. A FIH study of HP537 in cancer patients is planned to start in 2024. HP537 structure will not be disclosed.



04 HP560


摘要标题:

Discovery of HP560, a novel BET inhibitor for the treatment of myelofibrosis


摘要作者:

J. Li, L. Fan, H. Yuan, Y. Huo, H. Yu, F. Wang, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China


摘要全文:

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by defective clonal hematopoiesis, bone marrow fibrosis, splenomegaly, severe anemia, and the propensity for transformation to acute myeloid leukemia (AML). Inhibitors targeting JAKs (Janus kinases) have revolutionized the treatment of MF, but are limited by modest eïcacy or acquired resistance after prolonged treatment. Here, we report a novel inhibitor, HP560 that targets BET (bromodomain and extra-terminal) proteins and shows promising therapeutic activities against MF and AML. Through engaging the bromodomain pocket of BET proteins in a competitive manner with acetylated histones, HP560 causes the disruption of BET proteins from chromatin. HP560 has high binding affinities for all BET proteins and strong anti-proliferative activity as well as synergistic anti-proliferative effect in combination with ruxolitinib, a JAK1/2 inhibitor. In an MF cell line derived tumor xenograft (CDX) mouse model, HP560 prolongs survival and improves splenomegaly and anemia, and these effects are enhanced when combined with ruxolitinib. HP560 also significantly and dose-dependently inhibits tumor growth in an AML CDX mouse model. Together, HP560 is a potent pan-BET inhibitor and can be developed as a monotherapy or in combination with a JAK inhibitor for the treatment of MF. HP560 structure will not be disclosed.



05 HP567


摘要标题:

Discovery of HP567, a highly potent, brain-penetrating, and H1047R-selective PI3Kα inhibitor for the treatment of tumors bearing H1047R mutation


摘要作者:

J. Li, L. Fan, C. Liu, Y. Luo, X. Chu, H. Yu, F. Wang, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China


摘要全文:

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT) is one of the most altered pathways in human cancer and its hyperactivation promotes tumor growth and survival. H1047R increases kinase activity and is the most common PI3Kα mutation with a mutation rate of 7.8% in all cancers, and 21%, 5% and 3% in breast cancer, endometrium, and ovarian cancer, respectively. Alpelisib is an FDA approved PI3Kα inhibitor targeting both wildtype (WT) and mutant PI3Kα, yet its clinical benefit is limited by the toxicities including hyperglycemia and rash (which are considered on target effects of WT- PI3Kα inhibition). Here, we report an allosteric and brainpenetrating PI3Kα inhibitor, HP567 that is 14-fold selective for PI3Kα H1047R over PI3Kα WT and is 80-fold selective over other PI3K isoforms. HP567 strongly inhibits proliferation and p-AKT (S473) in H1047R mutant cell lines with an average IC of 138 nM and 8 nM, respectively, and has no activity against PI3Kα WT cell lines. HP567 strongly inhibits growth of tumors bearing H1047R in multiple CDX models including breast cancers (MDA-MB-453, T47D, and CAL-148), ovarian cancer (SK-OV-3), tongue squamous cell carcinoma (CAL-33), and a brain-metastatic breast cancer (MDA-MB-453), without causing hyperglycemia or increases in plasma insulin levels. In conclusion, HP567 is a novel, potent, and brain-penetrating PI3Kα H1047R selective inhibitor. The pre-clinical data supports the clinical development of HP567 for the treatment of tumors bearing PI3Kα H1047R mutations. Structure of HP567 will not be disclosed.



06 HC-X029


摘要标题:

Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC


摘要作者:

J. Li, Z. Tu, W. Du, X. Xiang, Z. Wen, Y. You, L. Zhao, Y. Chen, C. Yang, H. Yuan, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China


摘要全文:

Prostate cancer is the second most commonly diagnosed cancer and the second leading cause of cancer death among men worldwide. Androgens play an important role in the development and progression of prostate cancers and targeting androgen receptor (AR) signaling axis over decades has remained a mainstay of prostate cancer therapy. Next generation hormonal agents (NHAs) enzalutamide and abiraterone have brought clinical beneíts for metastatic castrate-resistant prostate cancer (mCRPC) patients, AR axis-targeted therapy resistance is inevitable due to AR gene ampliícation or mutations. AR-V7 is the most clinically relevant AR splice variant associated with endocrine resistance and poor prognosis. AR-V7 constitutively activates AR signaling and lacks the ligand binding domain (LBD) where hormones and AR antagonists interact, resulting in resistance to AR signaling inhibitors (ARSi). Thus, AR-V7 is a promising therapeutic target to address ARSi resistance in mCRPC. We have discovered a highly potent AR-V7 proteolysis targeting chimera (PROTAC), HC-4955 that degrades both the wild-type AR (WT-AR) and AR-V7 mutant. HC-4955 degrades AR-V7 with DC50 < 5 nM. In silico molecular docking analysis predicts the binding of HC-4955 to the N-terminal domain of AR and then the essential amino acids contributed to HC-4955 binding are validated by mutational analysis studies. HC-4955 also potently degrades mutants of AR-LBD mutations including L702H and T878A and these mutations are also associated with ARSi resistance. HC-4955 strongly inhibits proliferation of ARSi-resistant prostate cancer cell lines with IC50 < 10 nM. HC-4955 shows a robust anti-tumor activity in the AR-V7-bearing 22Rv1 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models, with majority of the tumors completely regressed and > 90% AR-V7 expression decreased at 1-5 mg/kg (QD, PO) in these models. The pre-clinical results support the clinical development of HC-4955 for the treatment of mCRPC. Selected pre-clinical data along with the chemical structure of HC-4955 will be presented.


关于海创药业


海创药业(股票代码:688302.SH)是一家专注于癌症和代谢疾病的全球化创新型药物企业,以“创良药·济天下”为使命,以为患者提供安全、有效、可负担的药物为重点,致力于研发和生产满足重大临床需求、具有全球权益的创新药物。

公司拥有“PROTAC 靶向蛋白降解技术、氘代药物研发、靶向药物发现与验证及转化医学技术” 4 大核心技术平台,已申请PCT和中国发明专利200余项,获中国、美国、日本、欧洲等国家和地区专利授权90+项,现承担 2 项国家“重大新药创制”科技重大专项和多个省市级科研项目,拥有13项在研产品。公司管理团队核心成员多来自世界 500 强知名药企,具有丰富药物研发及管理经验。

公司现有产品管线中,AR抑制剂氘恩扎鲁胺(HC-1119)正在中国和全球开展两项用于治疗去势抵抗性前列腺癌的III期临床试验,其中中国III期临床试验已达到主要研究终点,临床III期数据入选2023年6月美国临床肿瘤学会(ASCO)年会,氘恩扎鲁胺HC-1119-04注册研究信息纳入2023版CSCO前列腺癌诊疗指南,氘恩扎鲁胺软胶囊新药上市申请于2023年11月获NMPA受理;URAT1抑制剂HP501单药用于治疗高尿酸血症/痛风已完成多项临床I/II期试验,正在积极推进II/III期临床试验相;HP501用于治疗痛风相关的高尿酸血症的临床II期试验于2023年12月获美国FDA批准;HP501联合非布司他片进行原发性痛风伴高尿酸血症的临床试验申请于2024年4月获NMPA批准;对消化道肿瘤具有潜在的治疗作用的HP558已在欧洲完成临床 I 期试验,II 期临床试验申请已经获NMPA批准;HP518是中国首款进入临床阶段的口服AR PROTAC在研药物,澳大利亚已完成用于治疗转移性去势抵抗性前列腺癌(mCRPC)的 I 期临床试验,澳大利亚临床I期数据入选2024年1月美国临床肿瘤学会泌尿生殖系统肿瘤研讨会(ASCO-GU),并入选2024年度美国ASCO大会;此外,HP518同适应症临床试验申请已获美国FDA批准,HP518中国临床试验申请于2023年11月获NMPA批准,2023年12月完成中国首例受试者给药。